Iontophoresis is a percutaneous absorption promoting system using electricity to externally stimulate a subject. Iontophoresis is based on the principle that forces act on charged molecules such that positively charged molecules migrate from an anode to a cathode and negatively charged molecules migrate from the cathode to the anode in an electric field developed between the anode and cathode when a subject is electrically energized, thereby accelerating the delivery of drug molecules through skin barrier. (Refer to “Journal of controlled release,” Vol. 18, 1992, pp. 213-220; “Advanced Drug Delivery Review,” Vol. 9, 1992, p. 119; and “Pharmaceutical Research,” Vol. 3, 1986, pp. 318-326).
As mentioned above, iontophoresis causes a current to flow between an anode and a cathode, thereby prompting a drug to migrate. In recent years, a constant current apparatus is used which maintains a constant current irrespective of differences in impedance from person to person. Because there is a correlation between the delivery speed of a drug and the amount of current, a constant current apparatus is capable of delivering a drug at a constant speed regardless of the impedance of a subject. As to irritation to the skin of a subject, a current density of about 0.2 mA/cm2 or less is considered low irritation. Safety is ensured by setting a current equal to or less than a value determined from the area of a preparation attached to the skin and a maximum current density (area of preparation×maximum current density≧the amount of current).
However, skin impedance varies from 100 kΩ to near 1 kΩ depending on the time length of hydration time, the time length of energization, the magnitude of current supplied, and location of the subject. If a skin has an impedance of 100 kΩ, a current of 1 mA means an application of a voltage of 100V to the skin, giving a very strong irritation to the subject. This irritation resulting from energization appears prominently at the initial energization, and may cause irritation that the subject cannot stand, even if the voltage and current are within normal ranges.
It is well known that abrupt supply of current at an initial energization causes strong irritation even though the magnitude of current is equal to or less than the aforementioned current density. A variety of measures have been proposed in order to reduce irritation of the skin. For example, Japanese Patent Laid-Open No. 5-49702 discloses an iontophoresis apparatus equipped with current adjusting means that causes a gradual change of current at the beginning of energization. Japanese Patent Laid-Open No. 5-245214 discloses an ion administering system in which constant voltage supplying means is used at the beginning of energization of a subject's body, and then constant current supplying means is used when the current reaches a predetermined value.
These prior art are intended to reduce uncomfortable irritation at the beginning of energization and supply a constant current for drug administration. Even if the current is set to a low current, the apparatus that uses current adjusting means at the beginning of energization as described as above may impress an intolerably high voltage on a subject, if a subject has a very high skin impedance at the beginning of energization. The system that switches from the constant voltage means to the constant current means may cause similar irritation if a constant, sufficiently high voltage is applied, and may require a long time before the current reaches the predetermined value if a constant, very low voltage is applied. Thus, a sufficient measure has not been taken in order to eliminate uncomfortable irritation and to promote highly efficient drug administration.
If a current is adjusted by allowing a sufficient margin against application of a high voltage at the beginning of energization, or a constant voltage is set to a sufficient low value at the beginning of energization, then it takes a longer time before a predetermined current is reached. Therefore, there may be a possibility that during the excess time, the effective blood concentration of drug cannot be attained despite the fact that drug is actually being administered.